Physiological Functions of TR2 and TR4 Orphan Nuclear Receptor

The human testicular receptor 2 and 4 (TR2 and TR4) are two evolutionarily related orphan nuclear receptors belonging to the same nuclear receptor subfamily (Lee et al. 2002, J Steroid Biochem Mol Biol 81(4–5), 291–308). They regulate gene expression by binding to DNA as homodimers or a heterodimer with each other. TR4 may also cross-talk with other nuclear receptors, to control its target genes. In vitro and in vivo studies have identified several TR4 target genes, including ciliary neurotrophic factor alpha (CNTFRα) (Young et al. 1997, J Biol Chem 272(5), 3109–3116), apolipoprotein E (ApoE) (Kim et al. 2003, J Biol Chem 278(47), 46919–46926) and phosphenolpyruvate carboxykinase (PEPCK) (Liu et al. 2007, Diabetes 56(12), 2901–2909). Recent studies using TR4 knockout (TR4–/–) mice suggested that TR4 may play essential roles in growth, development, and metabolism (Zhang et al. 2007, Mol Endocrinol 21(4), 908–920; Kim et al. 2005, Biochem Biophys Res Commun 328(1), 85–90; Chen et al. 2005, Mol Cell Biol 25(7), 2722–2732; Mu et al. 2004, Mol Cell Biol 24(13), 5887–5899; Collins et al. 2004, Proc Natl Acad Sci U S A 101(42), 15058–15063). Mice with a germline deletion of TR4 are viable but have high early postnatal mortality, growth retardation, and profound reduction in body weight. Further studies showed that TR4 plays essential roles in the development and functioning in the central nervous system (Chen et al. 2005, Mol Cell Biol 25(7), 2722–2732), such as proper myelination and oligodendrocyte differentiation (Zhang et al. 2007, Mol Endocrinol 21(4), 908–920). Studies also showed that TR4 is important for spermatogenesis in male mice (Mu et al. 2004, Mol Cell Biol 24(13), 5887–5899) and folliculogenesis in female mice (Chen et al. 2008, Mol Endocrinol 22, 858–867). In addition, TR4 might be involved in skeletal muscle function and bone remodeling. TR4 and TR2 also regulate embryonic and fetal globin gene transcription (Tanabe et al. 2002, EMBO J 21(13), 3434–3442; Tanabe et al. 2007, EMBO J 26(9), 2295–2306). Surprisingly, mice lacking TR2 are viable and have no serious developmental defects. Thus, TR2 may either not be important in spermatogenesis and testis development, or its roles may be compensated by other closely related proteins such as TR4. Therefore, this chapter will focus on the in vivo roles of TR4.